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Predictive Toxicogenomics Uses the Genetic Hand You're Dealt To

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Predictive Toxicogenomics Uses the Genetic Hand You're Dealt To StrapPredictive in here toxicogenomics like this Playing the genes you’re dealt Predictive toxicogenomics uses the genetic hand you’re dealt to forecast your reaction to environmental chemicals. Lisa Melton reports 62 | Chemistry World | July 2008 www.chemistryworld.org Every poker player knows that it In November 2000, with genomic have generated much attention, In short takes more than a lucky hand to information still hot off the especially in countries where win. You need to have the measure sequencers, the NIEHS launched a Researchers are using arsenic water poisoning is common, of your opponent and, crucially, toxicogenomics initiative to track their knowledge of how and population screening highly to understand the odds of beating the genomic responses to certain genes interact with the desirable.1 them. chemicals. Five US academic environment to predict a Most scientists agree the Toxicogenomic researchers are centres joined the consortium to person’s risk of disease time will come when individual using a similar approach to tackle harness microarray gene expression Scientists already toxicogenomic profiles will become disease. They know that nearly all profiling, proteomic technologies have the knowledge to a major tool in medicine. Cancer, diseases involve a combination of and bioinformatics to answer scour the human genome heart disease, Parkinson’s disease genetic factors and environmental perplexing gene–environment for toxic fingerprints and Alzheimer’s disease among hazards such as stress, drug side- questions. that could predict a many, are known to result from effects and even food molecules. Rebecca Fry’s work on arsenic relatively high risk of genes and the environment acting in The big question is how much exposure is a dramatic example of diseases, including some synergy. our health depends on the genetic the insights microarray profiling can neurodegenerative According to Helmut Zarbl, hand we are dealt at conception, and provide. ‘Could we, with a handful diseases and cancer a toxicogenomics researcher at how much on the toxic assault we of genes, figure out whether a baby Such tests could be the University of Medicine and experience throughout our lives. has been exposed to arsenic in the used to identify people Dentistry of New Jersey, US, It’s a complex mix which has, so far, womb?’ says Fry, a research scientist who should avoid researchers already have the been hard to quantify. at the Massachusetts Institute of exposure to related knowledge to scour the genome But toxicogenomics is now Technology, in Boston, US and part environmental risks for these toxic fingerprints. ‘The beginning to measure the influence of the NIEHS-funded consortium. Drug companies key is to connect those biological of these environmental and genetic Fry uncovered a ‘smoking gun’ for are using predictive response indicators to mechanisms factors. Researchers have revealed pre-natal arsenic exposure. Working toxicogenomics to find of disease. We [can] make informed that environmental factors can with Mathuros Ruchirawat of the those patients at risk of guesses as to which of the affected alter a person’s genetic makeup, Chulabhorn Research Institute an adverse reaction to biological networks lead to disease,’ particularly during very early, in Thailand, and Leona Samson, a drug he explains. developmental stages. And the director of the MIT’s Center for Zarbl has already pinned down genetic code, in turn, influences how Environmental Health Sciences, several molecular pathways that people will respond to a particular she studied mothers and their may boost the risk of breast cancer. drug treatment, or determine the offspring living in a province of Among them is the hormone impact of exposure to a toxin. Thailand where tin mining leads prolactin. Rat strains in which William Suk, a toxicogenomic to heavy arsenic contamination in prolactin signalling is strongly researcher from the US National groundwater. Arsenic exposure activated are prone to develop Institute of Environmental Health increases cancer risk later in life. mammary carcinomas, Zarbl has Sciences (NIEHS) in Research It is possible to single out shown.2 And drugs known to Triangle Park, North Carolina, US, newborns exposed to arsenic in increase prolactin levels in serum describes it as a ripple effect. ‘It’s the womb, says Fry. She found a also boost the risk of breast cancer, about understanding environmental subset of 11 genes – mostly related and he is going one step futher – exposure and how it cascades to inflammation and stress response Microarrays allow using toxicogenomic approaches to through the [human] system over – that are dramatically altered researchers to track search for compounds that dampen time to cause disease,’ he says. ‘If if exposure has taken place. The thousands of genes at a those gene expression profiles. you can understand where the results published in PLoS Genetics time Spotting toxicant signatures and ripples are, you can understand how to smooth the bumps and prevent disease,’ he adds. The consequences of toxicogenomics are immediate and practical. If a person is genetically susceptible to Parkinson’s disease, for example, they would do well to avoid certain pesticides that ramp up their risk of developing the condition. Understanding the interplay of genetics and toxicology in this way could help millions to stay healthier for longer. Early encounters The completion of the human genome sequence, coupled with powerful gene chip technologies helped kick-start a new era in toxicogenomic research. Until then, investigators had been interrogating one gene at a time. Microarrays allowed them to ramp up the numbers, tracking thousands of genes at once. LIBRARY PHOTO SCIENCE / PASIEKA ALFRED www.chemistryworld.org Chemistry World | July 2008 | 63 StrapPredictive in here toxicogenomics like this susceptibilities will, eventually, provide people with individualised advice on how to prevent disease. ‘If a person carries a combination of genes that puts them at higher risk of disease with certain type of environmental exposure, then we could take steps either to reduce their exposure or use dietary interventions or drugs to counter the effects of that exposure,’ Zarbl explains. Small dangers But environmental hits are minute and take place over long periods. They could be fiendishly difficult to track. ‘Dose is always the problem in toxicology,’ says Andrew Smith, a toxicologist from the MRC Toxicology Unit, University of Leicester, UK. ‘When you study environmental toxins at such low level, are they of any significance? Putting all the data together to create a feasible picture is mind-bogglingly difficult.’ Working with Smith at the University of Leicester is molecular biologist Tim Gant. He points out that natural and innocuous fluctuations in the environment, for instance, temperature changes, also prompt gene expression changes. ‘Just because you can measure loads of genes going up or down doesn’t mean anything. The organism may be responding in a perfectly natural way,’ he says. But Gant is impressed by the dramatic speed with which pharmaceutical compounds trigger changes in gene expression. ‘You can see gene expression patterns that predict pathology [changing] very ALAMY / HOWARD A GEOFF quickly, within minutes, and it is possible to quantify these changes.’ and again somebody comes into Toxicogenomics can testing could be an obstacle. Most He is focusing his research the clinic with an overdose and identify those at risk of microarray analyses in humans have, efforts on anti-cancer agents. toxicity,’ notes William Kaufmann, developing cancer from thus far, used biopsies. Kaufman Very unpleasant side-effects of a professor of pathology and arsenic exposure via is pursuing the idea that if toxicity doxorubicin, a compound used laboratory medicine. ‘It is the most drinking water patterns show up in blood cells, to treat many types of tumours, common cause of acute liver failure, these would provide an easy-to- are well-known in the clinic but it’s not clear why some people access, surrogate marker for what is – the drug causes vomiting and react with a toxic response and going on in other tissues. hair-loss. But the cardiac toxicity others don’t.’ associated with this compound is His team at the University of Doomed drugs not understood at the molecular North Carolina at Chapel Hill, Early alarm bells to warn of toxicity level. Using microarray data, Gant US has identified a clear gene could also avoid the blind alleys and his colleagues have tracked gene expression pattern or signature for that plague drug discovery (see expression changes in heart cells. liver toxicity in mice treated with Chemistry World, June 2007, p58). At ‘These gene expression patterns tell sub-lethal doses of paracetamol. the early phases, the rate of attrition us about the potential mechanisms If the same patterns crop up in is astonishingly high. According that underpin those harmful humans, it will be possible to warn to Adriano Henney, AstraZeneca’s changes in cardiac cells,’ he explains. those people who may be at risk director of global discovery, enabling Even widely-prescribed and should avoid taking the drug; capabilities and sciences, most drugs, such as paracetamol, doctors could soon be running lab- compounds directed at novel targets are astonishingly toxic to some on-a-chip tests to screen for this type will never make it to pharmacists’ individuals. ‘People are given of toxicity. shelves. ‘60 per cent of compounds paracetamol all the time and now But in the clinic, tissue access for fail at the preclinical stage. Toxicity 64 | Chemistry World | July 2008 www.chemistryworld.org Predictive toxicogenomics is the main reason,’ he notes. Researchers at the Abbot Laboratories in Abbot Park, Illinois, US are wielding toxicogenomic tools to weed out the bad from the maybes. ‘If we do a toxicology study and some toxicity occurs, we can use gene expression analysis to understand the mechanism,’ explains Jeff Waring, group leader of Abbot’s toxicogenomics division. ‘Is the toxicity an on-target effect? If so, that may not be a good target to pursue,’ he points out.
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